1 Zyvox™ (linezolid) Tablets, injection, suspension NDAs 21-130, 21-131, 21-132 FDA presentation...
-
Upload
marylou-preston -
Category
Documents
-
view
215 -
download
1
Transcript of 1 Zyvox™ (linezolid) Tablets, injection, suspension NDAs 21-130, 21-131, 21-132 FDA presentation...
1
Zyvox™ (linezolid)Tablets, injection, suspension
NDAs 21-130, 21-131, 21-132
FDA presentation
Anti-Infective Drugs Advisory Committee
March 24, 2000
2
Overview
• Clinical pharmacology
• Clinical/statistical analyses of efficacy
• Clinical/statistical analyses of safety
• Development of resistance
3
Clinical pharmacology:Pharmacokinetics
IV PO
Tmax (h) 0.5 1.0
Cmax (g/mL) 15 21
Cmin (g/mL) 3.7 6.2
T1/2 (h) 4.8 5.4
4
Clinical pharmacology:Pharmacokinetics
• With 600 mg bid dosing:– AUC (PO) = 68 - 209 µg·h/mL– After normalization for body weight,
AUC = 11.2 - 23.8 µg·h/mL
5
Clinical pharmacology:Metabolism and excretion
• Metabolism– two major metabolites; toxicity not characterized
• Excretion• 35% in urine as parent drug• 50% in urine as metabolites• 10% in feces as metabolites• Metabolites accumulate in patients with renal
impairment
6
Efficacy Analyses
7
Clinical studies
• Community-acquired pneumonia– Study 33 (CAP in inpatients)– Study 51 (CAP in outpatients)
• Hospital-acquired pneumonia (Study 48A)• Skin/skin structure infections
– Studies 39A/39 (uncomplicated SSSI)– Study 55 (complicated SSSI)
• MRSS infections (Study 31)• VRE infections (Studies 54A/54)
8
Differences in outcome assessment
Sponsor FDA
Alive at TOC but no post-baselineassessment
Failure Missing*
Alive at EOT but died before TOC Missing* Failure
D/C’d for lack of efficacy Generallyfailure
Failure
*failure under certain pre-specified circumstances
9 13
Analytic populations
Randomized patients
ITT (all treated patients)
MITT (pathogen isolated)
ITT (all treated patients)
CE (meet baseline and post-baseline criteria)
ME(susceptible pathogen isolated
within baseline window)
10
Community-acquired pneumonia
11
Community-acquired pneumonia (Study 33)
• Population: 747 inpatients with CAP
• Design: Multi-center, multi-national, randomized, comparative, open-label
• Treatment arms (7-14 d treatment duration)– Linezolid 600 mg IV q12h /600 mg po q12h
– Ceftriaxone 1 g IV q12h /Cefpodoxime 200 mg po bid
Aztreonam allowed for Gram-negative infections
• 1º endpoint: Microbiologic outcome
12
Study 33 (Inpatient CAP)Demographics
Linezolid CeftriaxoneN % N %
Age (years)<18 8 2.1 5 1.4
18-44 120 31.5 112 30.645-64 110 28.9 113 30.9>65 143 37.5 136 37.2
Mean SD 54.6 20.1 54.7 19.2
GenderMale 228 59.8 209 57.1
Female 153 40.2 157 42.9
RaceWhite 246 64.6 241 65.8Black 46 12.1 44 12.0
Asian/Pacific Islander 34 8.9 37 10.1Mixed 55 14.4 44 12.0
13
Study 33 (inpatient CAP) Patient populationsTotal Linezolid Ceftriaxone
ITT 747 381 366
MITT 254 128 126
CE 559 285 274
ME 191 92 99
14
Study 33 (inpatient CAP) Clinical efficacy results
81 84 86 87
77 7782 82
0
10
20
30
40
50
60
70
80
90
100
ITT MITT CE ME
Su
cces
s ra
te (
%)
Linezolid
Ceftriaxone
N = 330 313 109 117 285 274 92 99
Excludes patients with missing outcomes
Study 33 (inpatient CAP) 95% confidence intervals
-20 -15 -10 -5 0 5 10 15 20
`CE
ME
ITT
MITT
Difference in response rate between linezolid and ceftriaxone/cefpodoxime
FDA Sponsor
16
Study 33 (inpatient CAP)Results by pathogen (ME patients)
Linezolid Ceftriaxone
N % cured N % cured
S. pneumoniae 73 86.3 73 84.9
S. pneumoniae bacteremia 30 90.0 24 62.5
PRSP (PCN MIC 2) 5 60.0 2 100.0
S. aureus 21 85.7 19 68.4
S. aureus bacteremia 1 100.0 2 50.0
MRSA 1 100.0 0 -H. influenzae
no aztreonam87
62.557.1
1210
83.390.0
17
Study 33 (inpatient CAP)Subgroup analyses (CE patients)
Linezolid CeftriaxoneN % cured N % cured
Bacteremia 31 90.3 26 61.5
Age > 50 y 171 85.4 160 80.0
> 1 lobe involved 15 93.3 7 71.4
> 1 lung involved 10 90.0 7 71.4
RR > 30 29 79.3 31 74.2
Hypotensive 22 77.3 35 71.4
[BUN] > 7 mM 75 80.0 63 69.8
HIV+ 7 100.0 6 83.3
18
Study 33 (inpatient CAP)Effect of missing data
81
70
84
7177
66
7771
0102030405060708090
100
ITT ITT* MITT MITT*
Su
cces
s ra
te (
%)
LinezolidCeftriaxone
*Missing outcomes scored as failures
N = 330 313 381 366 109 117 128 126
19
Community-acquired pneumonia (Study 51)
• Study population: 540 outpatients with CAP
• Design: Multi-center, multi-national, randomized, comparative, evaluator-blind
• Treatment arms ( 10-14 d treatment duration)– Linezolid 600 mg po q12h
– Cefpodoxime 200 mg po q12h
• 1º endpoint: Clinical outcome
20
Study 51 (Outpatient CAP) Demographics
Linezolid CefpodoximeN % N %
Age (years)<18 0 -- 1 0.4
18-44 126 46.3 120 44.845-64 93 34.2 86 32.1>65 53 19.5 61 22.8
Mean SD 47.6 17.4 48.8 18.4
GenderMale 132 48.5 140 52.2
Female 140 51.5 128 47.8
RaceWhite 196 72.1 207 77.2Black 30 11.0 28 10.4
Asian/Pacific Islander 1 0.4 2 0.7Mixed 42 15.4 29 10.8
Not Allowed to Ask 3 1.1 2 0.7
21
Study 51 (outpatient CAP) Patient populationsTotal Linezolid Cefpodoxime
ITT 540 272 268
MITT 120 60 60
CE 421 213 208
ME 98 50 48
22
Study 51 (outpatient CAP) Clinical efficacy results
83 85 85 888781
9081
0102030405060708090
100
ITT MITT CE ME
Su
cces
s ra
te (
%)
LinezolidCefpodoxime
N = 227 222 54 52 213 208 50 48
Excludes patients with missing outcomes
Study 51 (outpatient CAP) 95% confidence intervals
-20 -15 -10 -5 0 5 10 15 20 25
`CE
ME
ITT
MITT
Difference in response rate between linezolid and cefpodoxime
FDA Sponsor
24
Study 51 (outpatient CAP)Results by pathogen (ME patients)
Linezolid Cefpodoxime
N % cured N % cured
S. pneumoniae 27 92.6 22 90.5
S. pneumoniae bacteremia 3 100.0 6 50.0
PRSP (PCN MIC 2) 0 - 0 -S. aureus 12 91.7 12 75.0
S. aureus bacteremia 0 - 0 -MRSA 1 100.0 1 0.0
H. influenzae 13 84.6 16 87.5
25
Study 51 (outpatient CAP)Subgroup analyses (CE patients)
Linezolid CefpodoximeN % cured N % cured
Bacteremia 3 100.0 5 60.0
Age > 50 y 91 85.7 98 93.9
> 1 lobe involved 46 80.4 39 87.2
> 1 lung involved 30 83.3 27 88.9
RR > 30 9 88.9 7 85.7
Hypotensive 8 75.0 12 83.3
[BUN] > 7 mM 26 76.9 23 95.7
HIV+ 4 75.0 2 100.0
26
Study 51 (outpatient CAP)Effect of missing data
83
69
8577
87
7281
70
0102030405060708090
100
ITT ITT* MITT MITT*
Su
cces
s ra
te (
%)
Linezolid
Cefpodoxime
*Missing outcomes scored as failures
N = 227 222 272 268 54 52 60 60
27
Hospital-acquired pneumonia
28
Hospital-acquired pneumonia (Study 48A)
• Study population: 396 patients with HAP
• Design: Multi-center, multi-national, randomized, comparative, double-blind
• Treatment arms (7-21 d treatment duration)– Linezolid 600 mg IV q12h ± Aztreonam 1-2 g IV q8h
– Vancomycin 1 g IV q12h ± Aztreonam 1-2 g IV q8h
• 1° endpoints: Clinical/microbiologic outcomes
29
Study 48A (HAP) Demographics
Linezolid VancomycinN % N %
Age (years)18-44 34 16.7 43 22.345-64 53 26.1 48 24.9>65 116 57.1 102 52.8
Mean SD 62.8 18.0 61.3 18.7
APACHE II 15.7 6.5 15.5 6.9
GenderMale 142 70.0 131 67.9
Female 61 30.0 62 32.1
RaceWhite 181 89.2 170 88.1Black 11 5.4 10 5.2
Asian/Pacific Islander 1 0.5 1 0.5Mixed 7 3.4 10 5.2
Not Asked 3 1.5 2 1.0
30
Study 48A (HAP) Patient populationsTotal Linezolid Vancomycin
ITT 396 203 193
MITT 177 94 83
CE 225 122 103
ME 95 54 41
ME2 42 22 20
31
Study 48A (HAP) Clinical efficacy results
4957 57
6772
45 46
60 63 65
0102030405060708090
100
ITT MITT CE ME ME2
Su
cces
s ra
te (
%)
LinezolidVancomycin
N = 174 164 82 72 122 103 54 41 22 20
Excludes patients with missing outcomes
Study 48A (HAP) 95% confidence intervals
-20 -15 -10 -5 0 5 10 15 20 25 30
`CE
ME
ITT
MITT
Difference in response rate between linezolid and vancomycin
FDA Sponsor
33
Study 48A (HAP)Results by pathogen (ME patients)
Linezolid Vancomycin
N % cured N % cured
S. pneumoniae 9 100.0 10 90.0
PRSP 2 100.0 0 -
S. aureus 38 60.5 23 60.9
MRSA 22 59.1 10 70.0
34
Study 48A (HAP)Subgroup analyses (ME patients)
Linezolid Vancomycin
N % cured N % cured
Bacteremia 4 50.0 6 66.7
Ventilator-associatedpneumonia
33 60.6 22 40.9
VAP with MRSA 16 62.5 5 60.0
APACHE II11
12-1516-1920
18121013
72.266.760.061.5
121658
83.375.040.025.0
35
Study 48A (HAP)Subgroup analyses (MITT patients)
Linezolid Vancomycin
N % cured N % cured
Bacteremia 10 50.0 10 40.0
Ventilator-associatedpneumonia
56 53.6 46 30.4
VAP with MRSA 21 52.4 17 29.4
APACHE II11
12-1516-1920
21191526
71.457.953.346.2
19231218
73.756.525.016.7
36
Study 48A (HAP)Effect of missing data
4942
5750
4538
4640
0102030405060708090
100
ITT ITT* MITT MITT*
Su
cces
s ra
te (
%)
LinezolidVancomycin
*Missing outcomes scored as failures
N = 174 164 203 193 82 72 94 83
37
Study 48A (HAP) Mortality rates
18
5
25
9
0102030405060708090
100
All causes Due to initial infection
Mor
talit
y ra
te (
%)
LinezolidVancomycin
N = 203 193 203 193
38
Uncomplicated skin and skin structure infections (uSSSI)
39
Study 39A/39 (uSSSI)Description
• Population: 753 North American (39A),
332 Non-North American patients (39)• Design: Multi-center, randomized,
comparative, double-blind• Treatment arms (7-14 d treatment duration)
– Linezolid 400 mg po q12h
– Clarithromycin 250 mg po q12h
• 1º endpoints: Clinical/microbiologic outcomes
40
Study 39A (uSSSI) Demographics
Linezolid ClarithromycinN % N %
Age (years)18-44 212 55.5 200 53.945-64 109 28.5 121 32.6>65 61 16.0 50 13.5
Mean SD 44.1 17.1 43.9 17.0
GenderMale 219 57.3 197 53.1
Female 163 42.7 174 46.9
RaceWhite 318 84.1 322 87.0Black 43 11.4 31 8.4
Asian/Pacific Islander 2 0.5 3 0.8Mixed 12 3.2 12 3.2
Not Allowed to Ask 3 0.8 2 0.5
41
Study 39A (uSSSI) Patient populations
Total Linezolid Clarithromycin
ITT 753 382 371
CE 627 320 307
ME 210 97 113
42
Study 39A (uSSSI) Clinical efficacy results
86 88 8784 85 86
0102030405060708090
100
ITT CE ME
Su
cces
s ra
te (
%)
LinezolidClarithromycin
N = 341 322 320 307 97 113
Excludes patients with missing outcomes
Study 39A (uSSSI)95% confidence intervals
-20 -15 -10 -5 0 5 10 15 20
`
CE
ME
ITT
Difference in response rate between linezolid and clarithromycin
FDA Sponsor
44
Study 39A (uSSSI) Results by pathogen
Linezolid Clarithromycin
N % cured N % cured
S. aureus 93 86.0 105 84.8
MRSA 0 - 0 -
S. pyogenes 5 100.0 11 90.9
45
Study 39A (uSSSI)Effect of missing data
8677
84
73
0102030405060708090
100
ITT ITT*
Su
cces
s ra
te (
%)
LinezolidClarithromycin
*Missing outcomes scored as failures
N = 341 322 382 371
46
Study 39 (uSSSI) Demographics
Linezolid ClarithromycinN % N %
Age (years)18-44 99 59.6 103 62.045-64 48 28.9 50 30.1>65 19 11.4 13 7.8
Mean SD 41.7 16.3 41.1 16.9
GenderMale 95 57.2 90 54.2
Female 71 42.8 76 45.8
RaceWhite 88 53.0 85 51.2Black 10 6.0 11 6.6
Asian/Pacific Islander 45 27.1 46 27.7Mixed 22 13.3 23 13.9
Not Allowed to Ask 1 0.6 1 0.6
47
Study 39 (uSSSI) Patient populations
Total Linezolid Clarithromycin
ITT 332 166 166
CE 254 127 127
ME 101 43 58
48
Study 39 (uSSSI) Clinical efficacy results
88 899591 90
97
0102030405060708090
100
ITT CE ME
Su
cces
s ra
te (
%)
LinezolidClarithromycin
N = 148 149 127 127 43 58
Excludes patients with missing outcomes
Study 39 (uSSSI)95% confidence intervals
-20 -15 -10 -5 0 5 10 15 20
`
CE
ME
ITT
Difference in response rate between linezolid and clarithromycin
FDA Sponsor
50
Study 39 (uSSSI) Results by pathogen
Linezolid Clarithromycin
N % cured N % cured
S. aureus 39 97.4 54 96.3
MRSA 1 100.0 4 100.0
S. pyogenes 7 85.7 7 100.0
51
Complicated skin and skin structure infections (cSSSI)
52
Complicated skin/skin structure infections (Study 55)
• Population: 819 patients with cSSSI
• Study design: Multi-center, multi-national, randomized, comparative, double-blind
• Treatment arms (10-21 d treatment duration)– Linezolid 600 mg IV q12h / Linezolid 600 mg po bid
– Oxacillin 2 g IV q6h / Dicloxacillin 500 mg po q6h
• 1° endpoints: Clinical/microbiological outcomes
53
Study 55 (cSSSI) Demographics
Linezolid OxacillinN % N %
Age (years)18-44 194 48.5 180 43.045-64 139 34.8 133 31.7>65 67 16.8 106 25.3
Mean SD 46.8 17.1 49.2 18.5
GenderMale 252 63.0 255 60.9
Female 148 37.0 164 39.1
RaceWhite 227 56.8 230 54.9Black 49 12.3 69 16.5
Asian/Pacific Islander 38 9.5 42 10.0Mixed 84 21.0 76 18.1
Not Allowed to Ask 2 0.5 2 0.5
54
Study 55 (cSSSI)Patient populations
Total Linezolid Oxacillin
ITT 819 400 419
ITT-prime 629 316 313
CE 487 245 242
ME 209 101 108
55
Study 55 (cSSSI) Clinical efficacy results
85 86 9085
79 82 85 82
0102030405060708090
100
ITT ITT-prime CE ME
Su
cces
s ra
te (
%)
LinezolidOxacillin
N = 327 348 269 267 245 242 101 108
Excludes patients with missing outcomes
Study 55 (cSSSI) 95% confidence intervals
-20 -15 -10 -5 0 5 10 15 20
`CE
ME
ITT
ITT-prime
Difference in response rate between linezolid and oxacillin/dicloxacillin
FDA Sponsor
57
Study 55 (cSSSI) Results by pathogen
Linezolid OxacillinN % cured N % cured
S. aureus 83 88.0 84 85.7
MRSA 3 66.7 0 -
S. pyogenes 26 69.2 28 75.0
S. agalactiae 6 100.0 6 50.0
E. faecalis 2 0.0 5 80.0
E. faecium 2 50.0 0 -
58
Study 55 (cSSSI)Subgroup analyses
Linezolid Oxacillin
N % cured N % cured
Age 65 38 86.8 62 82.3
Diabetes mellitus 61 78.7 65 67.7
Peripheralvascular disease
10 60.0 18 44.4
59
Study 55 (cSSSI)Effect of missing data
85
70
86
7379
65
82
70
0102030405060708090
100
ITT ITT* ITT-prime ITT-prime*
Su
cces
s ra
te (
%)
LinezolidOxacillin
*Missing outcomes scored as failures
N = 327 348 400 419 269 267 316 313
60
Methicillin-resistant staphylococcal species (MRSS)
infections
61
MRSS infections(Study 31)
• Population: 460 patients with MRSS infection (Pneumonia, SSSI, UTI, BUO)
• Design: Multi-center, multi-national, randomized, comparative, open-label
• Treatment arms (7-28 treatment duration)– Linezolid 600 mg IV q12h
– Vancomycin 1 g IV q12h
– Concomitant aztreonam/gentamicin allowed
– 1° endpoints: Clinical/microbiologic outcomes
62
Study 31 (MRSS) Demographics
Linezolid VancomycinN % N %
Age (years)15-44 32 13.3 59 26.845-64 78 32.5 52 23.6>65 130 54.2 109 49.5
Mean SD 63.9 16.1 59.8 20.2
GenderMale 143 59.6 131 59.5
Female 97 40.4 89 40.5
RaceWhite 195 81.3 168 76.4Black 18 7.5 30 13.6
Asian/Pacific Islander 4 1.7 5 2.3Mixed 23 9.6 17 7.7
63
Study 31 (MRSS)Patient populationsTotal Linezolid Vancomycin
ITT 460 240 220
MITT 301 157 144
CE 241 116 125
ME 126 59 67
64
Study 31 (MRSS) Clinical efficacy results
61 59
80 76
63 6672 72
0102030405060708090
100
ITT MITT CE ME
Su
cces
s ra
te (
%)
Linezolid
Vancomycin
N = 181 160 128 112 116 125 59 67
Excludes patients with missing outcomes
Study 31 (MRSS)95% confidence intervals
-25 -20 -15 -10 -5 0 5 10 15 20 25
`CE
ME
ITT
MITT
Difference in response rate between linezolid and vancomycin
FDA Sponsor
66
Study 31 (MRSS)Results by pathogen (ME patients)
Linezolid Vancomycin
N % cured N % cured
S. aureus 52 76.9 57 71.9
MSSA 1 0.0 0 -
MRSA 51 78.4 57 71.9
MRSE 7 71.4 9 77.8
67
Study 31 (MRSS)Results by pathogen (MITT patients)
Linezolid Vancomycin
N % cured N % cured
S. aureus 112 58.0 94 64.9
MSSA 4 75.0 3 66.7
MRSA 104 55.8 88 65.9
MRSE 14 57.1 13 76.9
68
Study 31 (MRSS)Outcome by site of MRSA infection (ME)
Linezolid VancomycinN % cured N % cured
All sources 51 78.4 57 71.9
PneumoniaBacteremic
103
90.0 100.0
173
70.666.7
SSSIBacteremic
334
78.850.0
332
72.7100.0
UTI 0 - 2 100.0
BUO 2 100.0 1 100.0
OtherBacteremic
63
50.033.3
44
50.050.0
69
Study 31 (MRSS)Outcome by site of MRSA infection (MITT)
Linezolid VancomycinN % cured N % cured
All sources 104 55.8 88 65.9
PneumoniaBacteremic
288
42.950.0
285
53.640.0
SSSIBacteremic
527
69.242.9
443
77.3100.0
UTIBacteremic
61
33.30.0
40
100.0-
BUO 5 40.0 4 40.0
OtherBacteremic
136
46.250.0
76
42.950.0
70
Study 31 (MRSS)Effect of missing data
61
46
59
48
63
46
66
51
0102030405060708090
100
ITT ITT* MITT MITT*
Su
cces
s ra
te (
%)
LinezolidVancomycin
*Missing outcomes scored as failures
N = 181 160 240 220 128 112 157 144
71
Vancomycin-resistant enterococcal (VRE) infections
72
VRE infections (Study 54A)
• Population: 145 adult patients with known or suspected VRE infection (SST, UTI, BUO, IABD)
• Design: Multi-center, randomized, dose-comparison, double-blind, superiority
• Treatment arms– Linezolid 600 mg IV q12h
– Linezolid 200 mg IV q12h
Concomitant aztreonam or aminoglycosides allowed
• 1º endpoint: Clinical outcome
73
Study 54A (VRE) Demographics
High Dose Low DoseN % N %
Age (years)18-44 12 15.2 10 15.245-64 21 26.6 20 30.3>65 46 58.2 36 54.5
Mean SD 63.8 16.6 63.6 18.2
GenderMale 36 45.6 30 45.5
Female 43 54.4 36 54.4
RaceWhite 60 75.9 49 74.2Black 18 22.8 15 22.7
Asian/Pacific Islander 0 -- 1 1.5Mixed 1 1.3 1 1.5
74
Study 54A (VRE)Patient populations
Total High-dose(600 mg)
Low-dose(200 mg)
ITT 145 79 66
MITT-VRE 117 65 52
BacteremicMITT-VRE
34 18 16
75
Study 54A (VRE) Efficacy results
6759
52
29
0102030405060708090
100
MITT-VRE MITT-VRE (bacteremic)
Su
cces
s ra
te (
%)
High-doseLow-dose
p=0.16 p=0.15
N = 58 46 17 14
Excludes patients with missing outcomes
76
Study 54A (VRE)Results by pathogen
High-dose(600 mg)
Low-dose(200 mg)
N % cured N % cured
VanR E. faecium 57 66.7 45 53.3
VanR E. faecalis 4 75.0 2 0.0
77
Study 54A (VRE)Outcome by site of VRE infection
High-dose(600 mg)
Low-dose(200 mg)
N % cured N % cured
MITT-VRE (All sites) 58 67.2 46 52.2
BUO 10 50.0 7 28.6
SSTI 13 69.2 5 100.0
UTI 19 63.2 20 60.0
Pneumonia 3 66.7 1 0.0
Other* 13 84.6 13 38.6
*predominantly complicated IABD infection
78
Covariate analyses
• Covariate analyses were not prespecified• Multivariate analysis performed by FDA
using:– Risk of mortality at baseline– 1º diagnosis– Age, sex, weight– Bacteremia
• Adjusted and unadjusted results consistent
79
Study 54A (VRE)Effect of missing data
6760 59 5652
46
29 25
0102030405060708090
100
MITT-VRE MITT-VRE*
VREbacteremia
VREbacteremia*
Su
cces
s ra
te (
%)
High-doseLow-dose
*Missing outcomes scored as failures
N = 58 46 65 52 17 14 18 16
80
Study 54A (VRE)All-cause mortality rates
0102030405060708090
100
MITT-VRE MITT-VRE (bacteremic)
All-
cau
se m
orta
lity
rate
(%
)
High-doseLow-dose
N = 65 52 18 16
4/18 9/1618/5216/65
81
Causes of death in patients with VRE bacteremia
• High dose– VRE infection (1)
– Sepsis (2)
– Respiratory failure (1)
• Low dose– VRE infection (3)
– Sepsis (1)
– Pneumonia (1)
– GVHD (1)
– AIDS (1)
– Gastric cancer (1)
– Liver rejection (1)
82
Covariate analysis of mortality in bacteremic patients
• Not prespecified
• Covariates included:– Risk of mortality at baseline– Age– Sex
• Adjusted and unadjusted results consistent
83
History: Studies 54A & 54• Study 54 originally planned for 500 patients
• In 6/99, blinded decision to submit patients already enrolled as Study 54A (145 patients) – Submitted as stand-alone study– “all alpha spent” on this trial
• Study 54 continued as “supportive trial”– Data on 82 patients submitted to FDA in 12/99– Bolstering NS results of 54A with these results
could correspond to multiple looks without appropriate (prespecified) statistical adjustment
84
Study 54 (VRE)Efficacy results
64 60
4942
0102030405060708090
100
MITT-VRE MITT-VRE*
Su
cces
s ra
te (
%)
High-doseLow-dose
*Missing outcomes scored as failures
N = 28 35 30 41
85
Safety analysis
• Clinical adverse events
• Laboratory adverse events
• Potential drug-drug interactions
86
Adverse events
87
Adverse events
57 60
31
68
47 475655
4334
62
41 4150
01020304050607080
Inci
denc
e (%
)
LinezolidComparator
88
Drug-related adverse events
21
32
1318 17
2522
11
18 16
8
1720
16
05
101520253035
Inci
denc
e (%
)
LinezolidComparator
89
Discontinuations due to AEs
6
10
6
43
6 67
3
10
56
45
0
2
4
6
8
10
12
Inci
denc
e (%
)
LinezolidComparator
90
Discontinuations due to drug-related AEs
2.4
3.7
1.5
2.1
1
3.5
2.4
0.30.7
2.1
1.4
3.6
2.41.9
00.5
11.5
22.5
33.5
4
Inci
denc
e (%
)
LinezolidComparator
91
Discontinuations by adverse event
98
76 6 6
5 54
9
1
4 43 3
00123456789
10
Inci
den
ce (
%)
Linezolid
Comparator
Percentages are relative to number of patients who discontinued for any adverse event
92
Discontinuations by drug-related AE
22
1612 12
6 6 64
8
3
811
03 3
13
0
5
10
15
20
25
Inci
den
ce (
%)
Linezolid
Comparator
Percentages are relative to number of patients who discontinued for any drug-related adverse event
93
Laboratory findings
94
Comparator-controlled studies: Development of
thrombocytopenia*
3 3
5
11
32
12
6
2 21
0
2
4
6
8
10
12
Inci
denc
e of
thr
ombo
cyto
peni
a (%
)
LinezolidComparator
*Percentages are relative to number of patients with normal platelet counts at baseline
95
Comparator-controlled studies: Grade III thrombocytopenia*
0.5
0
0.5
2.5
0.30
0.30
1.6
0.40 0
0
0.5
1
1.5
2
2.5
3
Inci
denc
e of
thr
ombo
cyto
peni
a (%
)
LinezolidComparator
*Percentages are relative to number of patients with platelet count >50K at baseline
96
Effect of linezolid dose ondevelopment of
thrombocytopenia*13
56
3
5
11
32
3
0
2
4
6
8
10
12
14
Study54A
Allphase
IIIstudies
Study11
Allphase IIstudies
AllphaseII/III
studies
In
cid
ence
of
thro
mb
ocyt
open
ia (
%)
High-dose (>1 g/d)Low-dose (<1 g/d)
*Percentages are relative to number of patients with normal platelet counts at baseline
97
50100Platelet count x 10E-3 100
200
Pa
tie
nt
co
un
t
050
100
Platelet count x 10E-3
0
100
200
Pa
tie
nt
co
un
tResolution of thrombocytopenia in comparator-controlled phase III studies
Linezolid Comparator
M12600031
Sorting is by delta amount (smallest sort value at bottom)
Direction:
IncreaseNo changeDecreaseStartEnd
98
Summary: thrombocytopenia in linezolid-treated patients
• Incidence was 1 - 13% (grade III: 0-2.5%), depending on patient population
• Higher doses associated with incidence
• Thrombocytopenia appeared to resolve in patients with laboratory follow-up
• No related adverse events identified
• No apparent effect on other cell lines
99
Drug-drug interactions
100
MAO inhibition
Drug Type ofinhibition
Ki
MAO-A(µM)MAO-B
Cmax
(µM)
clorgyline IrreversibleMAO-A
0.0013 0.71 -
selegiline IrreversibleMAO-B
2 0.004 0.0045
linezolid Reversible 56 0.71 53.4
101
Linezolid-sympathomimetic amine interactions
Maximum change in systolic blood pressure
0
10
20
30
40
50
60
70
Maximum change in SBP
mm
Hg
Placebo
Phenylpropanolamine
Linezolid + placebo
Linezolid +phenylpropanolamine
102
Selected concomitant medications
0
5
10
15
20
25
LinezolidComparator
103
Potential drug-drug interaction events
• Database examined for potential MAOI-associated drug-drug interaction events
• Only small numbers of events found• No clear association between adverse events
examined and use of concomitant medications• Classic MAOI-associated events not seen
– No hypertensive crises
– No cases of serotonin syndrome
104
Linezolid resistance
105
Linezolid resistance
• Has been induced in laboratory
• Mechanism - G U on 23S rRNA
• Frequency < 1 in 109
• May result in cross-resistance to lincosamides and chloramphenicol
106
Linezolid resistancein clinical trials
• Only seen with Enterococcus spp.
• Fifteen cases in NDA database as of 12/31/99– 9/15 in compassionate use study (Study 25)
– 6/15 in dose-comparison studies (Studies 54A/54)
• Mean duration of therapy was 32 ± 9.9 d
• 14/15 cases were E. faecium; 1/15 was E. faecalis
• Increase in MIC to:– 8 µg/mL (6 isolates)
– 16 µg/mL (8 isolates)
– 32 µg/mL (1 isolate - E. faecalis)
107
Linezolid resistance in compassionate use trial (Study 25)
• 9/15 occurred during compassionate use– 8/9 E. faecium, 1/ 9 E. faecalis
• 6/9 patients considered failures
• 3/9 patients considered cured
108
Linezolid resistancein dose-comparison trials
• 6/15 occurred in studies 54A/54 (all E. faecium)
• 4 in low-dose group; 3/4 considered failures
• 2 in high-dose group; 1/2 considered failures
109
Linezolid Review Team
• Biopharmaceutics– Jenny Zheng, Ph.D.– Frank Pelsor, Ph.D. (TL)
• Chemistry– Jim Timper, M.S.– David Katague, Ph.D. (TL)
• Clinical– John Alexander, M.D.– David Ross, M.D., Ph.D.– Janice Soreth, M.D. (TL)
• Microbiology– Fred Marsik, Ph.D.– Albert Sheldon, Ph.D. (TL)
• Pharm/Tox– Ken Seethaler, Ph.D.– Robert Osterberg, Ph.D., R.Ph. (TL)
• Project Management– Beth Duvall-Miller, B.S.
• Statistics– Erica Brittain, Ph.D.
– Joel Jiang, Ph.D.– Daphne Lin, Ph.D. (TL)
• Supervisory Review– Gary Chikami, M.D. (DAIDP)– Sandra Kweder, M.D. (ODE IV)– Dianne Murphy, M.D. (ODE IV)